The present invention relates to therapeutic compositions and methods of treatment for conditions having an inflammatory component, and more specifically bone, joint or connective tissue inflammation. Examples of such conditions include arthritis, including osteoarthritis and rheumatoid arthritis, rheumatism, tendonitis, bursitis, degenerative spinal disc disease, and trauma to joints, tendons, and ligaments, including sports trauma.
Inflammation, as defined in Dorland""s Medical Dictionary, is xe2x80x9ca localized protective response elicited by injury or destruction of tissues which serves to destroy, dilute or wall off both the injurious agent and the injured tissue.xe2x80x9d It is characterized by dilation of the microvasculature, leakages of the elements of blood into the interstitial spaces, and migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema (redness), edema (fluid buildup), hyperalgesia (tenderness), heat, and pain. During this complex response, chemical mediators such as histamine, 5-hydroxytryptamine, various chemotactic factors, bradykinin, leukotrienes, and prostaglandins are liberated locally. Phagocytic cells migrate into the area, and cellular lysosomal membranes may be ruptured, releasing lytic enzymes. All of these events may contribute to the inflammatory response.
Inflammation in patients with rheumatoid arthritis probably involves the combination of an antigen (gamma globulin) with an antibody (rheumatoid factor) and complement causing the local release of chemotactic factors that attract leukocytes. The leukocytes phagocytose the complexes of antigen-antibody and complement and also release the many enzymes contained in their lysosomes. These lysosomal enzymes then cause injury to cartilage and other tissues, and this furthers the degree of inflammation. Cell mediated immune reactions may also be involved. Prostaglandins are also released during this process.
Prostaglandins, which are likely to be generated in inflammation, cause erythema and increase local blood flow. Two important vascular effects of prostaglandins that are not generally shared by other mediators of inflammation are a long-lasting vasodilator action and a capacity to counteract the vasoconstrictor effects of substances such as norepinephrine and angiotensin.
A number of mediators of inflammation increase vascular permeability (leakage) in the post-capillary and collecting venules. In addition, migration of leukocytes into an inflamed area is an important aspect of the inflammatory process.
Although osteoarthritis does not always include the same intense inflammatory component as rheumatoid arthritis, it does involve damage to cartilage and other tissues, resulting in pain, deformity, and limitation of motion of joints, in a similar fashion to rheumatoid arthritis.
Osteoarthritis is divided into two categories, primary and secondary osteoarthritis. In primary osteoarthritis, the degenerative wear-and-tear process generally occurs after the fifth and sixth decades, with no predisposing abnormality apparent. The cumulative effects of decades of use leads to the degenerative changes by stressing the integrity of the collagen matrix of the cartilage. Damage to the cartilage results in the release of enzymes that destroy collagen components. With aging, there is a decreased ability to restore and synthesize normal collagen structures.
Secondary osteoarthritis is associated with some predisposing factor responsible for the degenerative changes. Various predisposing factors in secondary osteoarthritis include congenital abnormalities in joint structure or function (e.g. excessive joint mobility and abnormally shaped joint surfaces), trauma (obesity, fractures along joint surfaces, surgery, etc.), crystal deposition, presence of abnormal cartilage, and previous inflammatory disease ofjoint (rheumatoid arthritis, gout, septic arthritis, etc.)
The causes of osteoarthritis are, thus, believed to include one or more of the following conditions or imbalances in the body""s chemistry: excessive mobility/joint instability, age-related changes in collagen matrix repair mechanisms, hormonal and sex factors, altered biochemistry, genetic predisposition, inflammation, fractures and mechanical damage, inflammatory joint disease, joint immobilization, poor nutritional history, and others.
As anyone who has been afflicted by this disease can attest, the onset of osteoarthritis can be very subtle, morning joint stiffness often being the first symptom. As the disease progresses, there is pain on motion of the involved joint, that is made worse by prolonged activity and relieved by rest. There is usually only minor inflammation.
The specific clinical picture varies with the joint involved. Disease of the hands leads to pain and limitation of use. Knee involvement produces pain, swelling, and instability. Osteoarthritis of the hip causes local pain and a limp. Spinal osteoarthritis is very common and may result in compression of nerves and blood vessels, causing pain and vascular insufficiency.
The inflammatory response is any response characterized by inflammation as defined above. It is well known to those skilled in the medical arts that the inflammatory response causes much of the physical discomfort, i.e., pain and loss of function, that has come to be associated with different diseases and injuries. Accordingly, it is a common medical practice to administer pharmacological agents which have the effect of neutralizing the inflammatory response. Agents having these properties are classified as anti-inflammatory drugs. Anti-inflammatory drugs are used for the treatment of a wide spectrum of disorders, and the same drugs are often used to treat different diseases. Treatment with anti-inflammatory drugs is not for the disease, but most often for the symptom, i.e., inflammation.
The anti-inflammatory, analgesic, and anti-pyretic drugs are a heterogeneous group of compounds, often chemically unrelated, which nevertheless share certain therapeutic actions and side-effects. Corticosteroids represent the most widely used class of compounds for the treatment of the inflammatory response. Proteolytic enzymes represent another class of compounds which are thought to have anti-inflammatory effects. Hormones which directly or indirectly cause the adrenal cortex to produce and secrete steroids represent another class of anti-inflammatory compounds. A number of nonhormonal anti-inflammatory agents have been described. These agents are generally referred to as non-steroidal anti-inflammatory drugs (NSAIDS). Among these, the most widely used are the salicylates. Acetylsalicylic acid, or aspirin, is the most widely prescribed analgesic-antipyretic and anti-inflammatory agent. Examples of steroidal and non-steroidal anti-inflammatory agents are listed in the Physicians Desk Reference, 54Edition, 2000 (see pp. 202 and 217 for an index of such preparations).
The natural and synthetic corticosteroid preparations cause a nunber of severe side effects, including elevation of blood pressure, salt and water retention, and increased potassium and calcium excretion. Moreover, corticosteroids may mask the signs of infection and enhance dissemination of infectious microorganisms. These hormones are not considered safe for use in pregnant females, and long-term corticosteroid treatment has been associated with gastric hyperactivity and/or peptic ulcers. Treatment with these compounds may also aggravate diabetes mellitus, requiring higher doses of insulin, and may produce psychotic disorders. Hormonal anti-inflammatory agents which indirectly increase the production of endogenous corticosteroids have the same potential for adverse side-effects.
NSAIDS are synthetic biochemical compounds which can be toxic at high doses with a wide spectrum of undesirable side-effects. For example, salicylates contribute to the serious acid-base balance disturbances that characterize poisoning by this class of compounds. Salicylates stimulate respiration directly and indirectly. Toxic doses of salicylates cause central respiratory paralysis as well as circulatory collapse secondary to vasomotor depression. The ingestion of salicylate may result in epigastric distress, nausea, and vomiting. Salicylate-induced gastric bleeding is well known. Salicylates can produce hepatic injury, and lead to a prolongation of clotting time. Therefore, aspirin should be avoided with patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency, or hemophilia, because the inhibition of platelet homeostasis by salicylates can result in hemorrhage. Salicylate intoxication is common, and over 10,000 cases of serious salicylate intoxication are seen in the United States every year, some of them being fatal, and many occurring in children. See Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9 Ed., 1992.
Another side effect of aspirin and other NSAIDs that is often not mentioned is their inhibition of cartilage repair (i.e. inhibition of collagen matrix synthesis) and acceleration of cartilage destruction in experimental studies. Since osteoarthritis is caused by a degeneration of cartilage, it appears that, while NSAIDs are fairly effective in suppressing the symptoms, they possibly worsen the condition by inhibiting cartilage formation and accelerating cartilage destruction. This adverse effect of NSAID therapy has been upheld in studies which have shown that NSAIDs use is associated with acceleration of osteoarthritis and increased joint destruction. Simply stated, NSAIDs appear to suppress the symptoms but accelerate the progression of osteoarthritis. Accordingly, in spite of the large number of anti-inflammatory agents that are currently available, there still exists a need for a safe, effective anti-inflammatory product which is free of side-effects and adverse reactions.
Natural ingredients, including Ayurvedic formulations, have been used to treat bone and joint inflammation, especially in eastern countries, and, increasingly, in western countries. Such natural ingredients include, for example, cartilage, chondroitin, glucosamine, proteolytic and other enzymes, and herbs, such as the gummy extract of B. serrata, Ashwagandha root and ginseng root. Although such natural ingredients generally do not lead to the kind of side effects observed with the steroidal and non-steroidal anti-inflammatory drugs (NSAIDS) discussed above, many of these natural ingredients do not always provide sufficient relief of pain or restoration of significant function and use of inflammed tissue, e.g., joints. However, glucosamine and chondroitin have been found to contribute to restoring such function and use.
Although glucosamine generally does not provide the same rapid temporary relief of inflammation and pain as aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS), it plays several key roles in the preservation and rebuilding ofjoint tissues. Namely, it stimulates the cartilage cells to produce glycosaminoglycans and proteoglycans, which maintain healthy joints and contribute to rebuilding connective tissue, and it is one of the main ingredients of the synovial fluid that lubricates and provides nutrients for the joint structures. By participating in the preservation and rebuilding ofjoint tissues, it is believed that glucosamine can contribute to long term relief of a wide range of degenerative and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, degenerative spinal disc disease, tendinitis, bursitis, and trauma to joints, tendons and ligaments, and may actually reverse the underlying disease process, in many cases.
Chondroitins, e.g. chondroitin sulfate, have also been found to play a role in the preservation and rebuilding ofjoint tissues. In a similar fashion to glucosamine, chondroitins have been found to stimulate cartilage cells to produce the needed proteoglycans and to inhibit the enzymes that break down proteoglycans. Chondroitin sulfate in particular also functions to draw fluid into the proteoglycan molecules. This fluid acts as a shock absorber for the joint tissue and also carries nutrients into the cartilage.
Although the administration of glucosamine appears to be an effective treatment for many conditions having an inflammatory component, it is not free of side effects. In that regard, it has been found that high blood serum levels of glucosamine can interfere with glucose regulation in both normal individuals and individuals with diabetes mellitus. The high levels of glucosamine can induce an insulin resistance response, resulting in reduced rates of insulin-mediated glucose uptake by the liver, skeletal muscle, and adipose tissue (fat cells). If uncontrolled, insulin resistance can lead to hyperglycemia and possibly glucose toxicity. In normal (i.e., non-diabetic) individuals, hyperglycemia can interfere with cellular metabolism and the mechanics for insulin-induced glucose disposal. The hyperglycemia itself can worsen insulin resistance, thus contributing to a vicious cycle that makes glycemic regulation more difficult. Moreover, hyperglycemia and insulin resistance are major contributing factor in the pathogenesis of non-insulin-dependant diabetes mellitus (NIDDM).
The effects of high glucosamine levels on patients with NIDDM are typically more pronounced, since such patients generally affect glycemic regulation with dietary control. Thus, in such patients the cause and effect of insulin resistance and hyperglycemia on each other result in worsening the diabetic state and making glycemic regulation more difficult. Moreover, clinical studies have shown that hyperglycemia is the cause of most if not all of the chronic complications of diabetes. Insulin resistance induced by high levels of glucosamine can also have dramatic effects on patients with insulin dependent diabetes mellitus (IDDM) by again initiating a vicious cycle that worsens the diabetic state and makes glycemic regulation more difficult, possibly leading to glucose toxicity.
Thus, there is a need for new treatments of conditions having an inflammatory component, such as inflammed bones and/or joints, that avoid the disadvantages of known treatments, including the disadvantages described above.
The present invention is a composition and method for the treatment of a condition having an inflammatory component. Treatment of such conditions in accordance with the present invention contributes to both long term relief of the symptoms associated with the inflammatory condition and restoration of finction and use of inflammed tissue (e.g., bones and joints), without the side effects attributable to more conventional steroidal anti-inflammatory drugs and NSAIDS, such as aspirin.
In one aspect, the invention relates to a controlled-release glucosamine composition which contains a therapeutically effective amount of a glucosamine component dispersed in a controlled-release matrix system capable of releasing the glucosamine in an amount and at a rate sufficient to maintain an effective glucosamine blood serum level over a designated time period. The controlled-release matrix system contains a controlled-release component which contains at least one water soluble cellulose polymer, preferably at least one water soluble high molecular weight cellulose polymer.
Preferably, the glucosamine component is selected from the group consisting of N-acetyl-D-glucosamine, glucosamine hydrochloride, glucosamine sulfate and mixtures thereof A typical dosage according to the invention ranges from about 2 mg to about 45 mg of glucosamine per kilogram of body weight per 24 hour period. Preferably, the daily dosage is from about 14 mg to about 29 mg and more preferably about 21 mg per kilogram of body weight.
The controlled-release component is preferably selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxy propyl cellulose (HPC), carboxy methyl cellulose (CMC), and mixtures thereof. The most preferred controlled-release component is HPMC.
The HPMC is preferably a high molecular weight HPMC, having an average molecular weight of at least about 25,000, more preferably at least about 65,000 and most preferably at least about 85,000.
The HPMC preferably consists of fine particulates having a particle size such that not less than 80% of the HPMC particles pass through an 80 mesh screen.
The HPMC can be included in an amount of from about 4 to about 24 wt %, preferably from about 6 to about 16 wt % and more preferably from about 8 to about 12 wt %, based upon total weight of the composition.
In a preferred embodiment, the controlled-release matrix system is capable of releasing the glucosamine at a substantially constant rate over the designated time period. Preferably, the controlled-release matrix system is capable of releasing the glucosamine at a substantially constant rate over a designated time period selected from about 6, 8, 12 and 24 hours. More preferably the designated time period is about 12 hours.
The composition is preferably in a form suitable for oral administration. This form can be a tablet and more preferably a tablet capable of releasing glucosamine at a substantially constant rate over a designated time period of about 12 hours. Such a tablet can contain HPMC, having an average molecular weight of about 85,000, as the controlled-release component in an amount of, for example, about 10 wt %.
In addition to the glucosamine component, the composition can optionally include a therapeutically effective amount of chondroitin sulfate. The daily dosage of chondroitin sulfate ranges from about 100 mg to about 2400 mg. Preferably, the daily dosage is from about 200 mg to about 1800 mg and more preferably about 1200 mg, based upon a 70 kg human or animal.
The invention also provides a unit dosage for controlled delivery of glucosamine which contains a therapeutically effect amount of a glucosamine component dispersed in a controlled-release matrix system containing a controlled-release component capable of providing a release profile which results in a substantially constant release of glucosamine over a designated time period.
The unit dosage is preferably in a form suitable for oral administration. More preferably, the unit dosage is a tablet. The tablet preferably contains about 8 to about 12 wt % HPMC, having a molecular weight of about 85,000, and is designed to release the glucosamine over about a 12 hour period.
In another aspect, the invention is a method for the treatment of conditions having an inflammatory component which involves: administering to a human or animal having a condition with an inflammatory component a composition which contains a therapeutically effective amount of a glucosamine component dispersed in a controlled-release matrix system capable of releasing the glucosamine in an amount and at a rate sufficient to maintain an effective glucosamine blood serum level over a designated time period, the controlled-release matrix system containing a controlled-release component which contains at least one water soluble cellulose polymer.
The composition being administered is preferably the controlled-release glucosamine composition, as described above, and more preferably the unit dosage, as described above.
In an especially preferred embodiment, the method also involves maintaining an effective glucosamine blood serum level, by continually repeating the administering step at the expiration of the designated time period, so as to relieve the inflammatory component of the condition. For example, where the designated time period is 12 hours, the method can be carried out by a continued regimen of administering one dosage every 12 hours to maintain a substantially constant release of glucosamine over a time sufficient to provide relief from the inflammatory condition.
In another aspect, the invention is directed towards a composition for the treatment of arthritis without adversely effecting glucose regulation, the composition containing a therapeutically effective amount of a glucosamine component dispersed in a controlled-release matrix system capable of releasing the glucosamine in an amount and at a rate sufficient to maintain an effective glucosamine blood serum level for treatment of arthritis, but not to exceed a glucosamine blood serum level which will affect an adverse change in glucose regulation, over a designated time period.
The adverse change in glucose regulation refers to increased difficulty in metabolizing blood serum glucose and can be manifested by increased insulin resistance. In such a case, the composition will release glucosamine in an amount and at a rate which provides a glucosamine blood serum level that does not exceed the level which will induce an insulin resistance response.
The composition according to this aspect of the invention can be used for the treatment of arthritis in humans and animals having both arthritis and a condition in which the ability to metabolize carbohydrates is reduced, such as, for example, diabetes or syndrome X, without adversely effecting glucose regulation, e.g., without inducing an insulin resistance response.
The composition in accordance with this aspect of the invention can include the controlled-release glucosamine composition, as described above, provided that the glucosamine release rate does not exceed a rate which results in an adverse change in glucose regulation, e.g., a rate which will induce an insulin resistance response. The rate of release of the glucosamine will preferably be less than about 100 micrograms/min/kg body weight, more preferably less than about 50 micrograms/min/kg body weight, and most preferably less than about 25 micrograms min/kg body weight.
The composition for treatment of arthritis is preferably in a form suitable for oral administration, more preferably in a tablet which contains a high molecular weight HPMC in an amount from about 8 to about 12 wt % as the controlled-release component. The tablet is preferably designed to release the glucosamine at a substantially constant rate over a time period of from about 8 to 12 hours, but not to exceed a rate which results in a glucosamine blood serum level sufficient to affect an adverse change in glucose regulation.
In yet another aspect, the invention is directed towards a method for the treatment of arthritis without adversely effecting glucose regulation, the method involving: administering to a patient having arthritis a composition which contains a therapeutically effective amount of a glucosamine component for the treatment of arthritis dispersed in a controlled-release matrix system capable of releasing the glucosamine in an amount and at a rate sufficient to maintain an effective glucosamine blood serum level for the treatment of arthritis, but not to exceed a glucosamine blood serum level which will affect an adverse change in glucose regulation, over a designated time period.
The composition being administered is preferably the composition for the treatment of arthritis, as described above. This composition is preferably administered orally in a tablet form, more preferably in a tablet which contains HPMC in an amount of from about 8 to about 12 wt %, as the controlled-release component The tablet is preferably designed to release the glucosamine at a substantially constant rate over a time period of about 8 to 12 hours, but not to exceed a rate of about 100 micrograms/min/kg body weight.
In a preferred embodiment, the method will also include maintaining an effective glucosamine blood serum level, by continually repeating the administering step at the expiration of the designated time period, so as to relieve the symptoms of arthritis.
The present invention provides compositions and methods of treatment for conditions having an inflammatory component, which does not have the side effects associated with conventional steroidal anti-inflammatory drugs and NSAIDs, such as aspirin. The present invention also provides the advantage of a composition and method of treatment for arthritis, which does not adversely effect glucose regulation, e.g., does not result in increased insulin resistance in either normal patients or patients with diabetes. Additionally, the present invention is directed to maintaining a substantially constant release rate of glucosamine to provide a better treatment for arthritis as a result of improved patient compliance, a dosage regimen that is easier to use and improved efficiency of the administered glucosamine.
Additional objects, advantages and novel features of the invention will be set forth in part in the description and examples which follow, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.